The glucocorticoid receptor (GR) is a member of the steroid thyroid nuclear hormone receptor superfamily, which includes, but is not limited to, mineral corticoid, androgen, progesterone and estrogen receptors. The glucocorticoid receptor is activated in vivo by binding of natural agonists such as cortisol and corticosterone. The glucocorticoid receptor may also be activated by binding of synthetic agonists such as dexamethasone, prednisone and prednisilone. Mifepristone is known to induce mixed GR passive antagonism, GR active antagonism, and GR agonism. Passive antagonism is the mechanism by which the formation of a ligand competent GR complex and the receptor nuclear translocation are blocked.
Currently available drugs that bind to the glucocorticoid receptor are typically cortisol analogues, which produce undesired side effects that are caused by: (1) unselective binding to other steroid receptors; and (2) failure to disassociate the different response elements when binding to the glucocorticoid receptor. Thus, there exists a need for compounds that selectively inhibit all glucocorticoid receptor-mediated nuclear functions.